Anti-cancer use of genetically modified human umbilical cord perivascular cells (hucpvc)

Abstract

Herein described is a method for treating cancer in a subject by administering a human umbilical cord perivascular cell (HUCPVC) that has been genetically modified to increase the expression of an oligonucleotide or a polypeptide such as an anti-cancer antibody.

1 . A method for treating cancer in a subject, comprising administering to the subject a human umbilical cord perivascular cell (HUCPVC) that has been genetically modified to increase the expression of an oligonucleotide or a polypeptide in said HUCPVC relative to a HUCPVC that has not been genetically modified, wherein said modified HUCPVC treats said cancer. 
     
     
         2 . The method of  claim 1 , wherein the HUCPVC is genetically modified to express a transgene that encodes an anti-cancer polypeptide. 
     
     
         3 . The method according to  claim 2 , wherein the anti-cancer polypeptide is an antibody or an anti-cancer fragment thereof. 
     
     
         4 . The method according to  claim 3 , wherein the anti-cancer polypeptide is an antibody or a fragment thereof that is an immune checkpoint inhibitor. 
     
     
         5 . The method according to  claim 3 , wherein the antibody or fragment thereof binds and inhibits an immune checkpoint selected from CTLA-4, PD-1, PD-1 receptor, PD-L1, PD-L2, CD20, CD25, CD27L, CD28, CD30L, CD40, CD40L, CD47, CD200, SIRPa, toll-like receptors TLR3, TLR7 and TLR8, VCP, PLIF, LSF-1, Nip, uromodulin, Fas, FasL, SIRPα, B7.1, and B7.2. 
     
     
         6 . The method according to  claim 5 , wherein the antibody or fragment thereof binds an immune checkpoint selected from CTLA-4, PD-1, PD-1 receptor and PD-1 receptor ligands designated PD-L1 and PD-L2. 
     
     
         7 . The method according to  claim 4 , wherein the immune checkpoint inhibitor is an antibody selected from ipilimumab (CTLA-4), atezolizumab (PD-1), pembrolizumab or nivolumab (PD-1 receptor), rituximab (CD20), and ofatumumab (CD20). 
     
     
         8 . The method according to  claim 5 , wherein the anti-cancer polypeptide is an antibody or fragment thereof that binds to a growth factor or a growth factor receptor. 
     
     
         9 . The method according to  claim 8 , wherein the antibody or fragment thereof binds to a growth factor selected from transforming growth factor-beta (TGF-β) superfamily, platelet derived growth factor (PGDF), insulin-like growth factors (IGFs), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), glucagon-like peptide 2 (GLP-2). 
     
     
         10 . The method according to  claim 9 , wherein the antibody is bevacizumab. 
     
     
         11 . The method according to  claim 8 , wherein the antibody or fragment thereof binds to a receptor for a growth factor selected from transforming growth factor-beta (TGF-β) superfamily, platelet derived growth factor (PGDF), insulin-like growth factors (IGFs), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), glucagon-like peptide 2 (GLP-2) 
     
     
         12 . The method according to  claim 11 , wherein the antibody or fragment thereof binds to the her-2 gene expression product. 
     
     
         13 . The method according to  claim 11 , wherein the HUCPVC has been genetically modified to produce the antibody trastuzumab. 
     
     
         14 . The method according to  claim 11 , wherein the HUCPVC has been genetically modified to produce the antibody pertuzumab. 
     
     
         15 . The method according to  claim 11 , wherein the antibody or fragment thereof binds to EGFR. 
     
     
         16 . The method according to  claim 15 , wherein the HUCPVC has been genetically modified to produce an EGFR antibody selected from cetuximab, panitumumab, matuzumab, necitumumab, nimotuzumab, and zalutumab. 
     
     
         17 . The method according to  claim 2 , wherein the anti-cancer polypeptide is an interleukin. 
     
     
         18 . The method according to  claim 17 , wherein the anti-cancer polypeptide is interleukin-2. 
     
     
         19 . The method according to  claim 2 , wherein the anti-cancer polypeptide is an interferon. 
     
     
         20 . The method according to  claim 2 , wherein the anti-cancer polypeptide is TRAIL. 
     
     
         21 . The method according to  claim 2 , wherein the anti-cancer polypeptide is a member of the tumour necrosis factor superfamily. 
     
     
         22 . The method according to  claim 2 , wherein the anti-cancer polypeptide is a decorin. 
     
     
         23 . The method according to  claim 2 , wherein the anti-cancer polypeptide is an antibody that binds a GD2 ganglioside. 
     
     
         24 . The method according to  claim 2 , wherein the anti-cancer polypeptide is an antibody that binds to and inhibits a baculoviral IAP repeat-containing protein selected from BIRC1, BIRC2, BIRC3, BIRC4, BIRC5 (survivin), BIRC6, BIRC7 and BIRC8. 
     
     
         25 . The method according to  claim 2 , wherein the anti-cancer polypeptide is an antibody that is basiliximab or daclizumab. 
     
     
         26 . The method according to  claim 2 , wherein the anticancer polypeptide is an Fc fusion protein comprising an anti-cancer polypeptide. 
     
     
         27 . The method according to  claim 2 , wherein the anti-cancer polypeptide is a fragment of a polypeptide involved in an interaction that supports cancer progression, the fragment being an antagonist of that interaction. 
     
     
         28 . The method according to  claim 2 , wherein the anti-cancer polypeptide stimulates growth of a cell type useful in cancer therapy selected from granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), erythropoietin (EPO), and thrombopoietin (TPO). 
     
     
         29 . The method of  claim 1 , wherein said oligonucleotide is selected from an RNA interference (RNAi) molecule capable of inhibiting oncogene expression. 
     
     
         30 . The method of  claim 29 , wherein said RNAi molecule is a small inhibitory RNA (siRNA) or short hairpin RNA (shRNA) molecule. 
     
     
         31 . The method of  claim 1 , wherein said method comprises administering a single dose of a composition comprising said HUCPVC to said subject. 
     
     
         32 . The method of  claim 1 , wherein said HUCPVC is administered as a vaccine to protect said subject. 
     
     
         33 . The method of  claim 1 , wherein said polypeptide is a cellular protein that acts as an antigen, thereby generating an immune response in said subject against said antigen. 
     
     
         34 . The method of  claim 1 , wherein said cell persists in said subject for greater than one week. 
     
     
         35 . The method of  claim 34 , wherein said HUCPVC persists in said subject for greater than one month. 
     
     
         36 . The method of  claim 35 , wherein said HUCPVC persists in said subject for greater than two months. 
     
     
         37 . The method of  claim 35 , wherein said HUCPVC persists in said subject for greater than six months. 
     
     
         38 . The method of  claim 1 , wherein said HUCPVC is administered to said subject intravenously, intramuscularly, orally, by inhalation, parenterally, intraperitoneally, intraarterially, transdermally, sublingually, nasally, transbuccally, liposomally, adiposally, opthalmically, intraocularly, subcutaneously, intrathecally, topically, or locally. 
     
     
         39 . The method of  claim 1 , wherein said HUCPVC evades immune recognition in said subject. 
     
     
         40 . The method of  claim 1 , wherein said subject is administered between 10 1  and 10 13  HUCPVCs per dose. 
     
     
         41 . The method of  claim 40 , wherein said subject is administered between 10 3  and 10 8  HUCPVCs per dose. 
     
     
         42 . The method of  claim 1 , wherein said HUCPVC has been genetically modified to express two or more oligonucleotides or polypeptides. 
     
     
         43 . The method of  claim 1  further comprising administering at least one mesenchymal stem cell (MSC), wherein said MSC is not a HUCPVC. 
     
     
         44 . The method of  claim 43 , wherein said MSC has been genetically modified to increase the expression of an oligonucleotide or a polypeptide in said MSC relative to a MSC that has not been genetically modified. 
     
     
         45 . The method of  claim 44 , wherein said MSC is isolated from bone marrow, umbilical cord blood, adipose tissue, embryonic yolk sac, placenta, skin, or blood. 
     
     
         46 . The method of  claim 1 , wherein said HUCPVC is administered with a pharmaceutically acceptable carrier or excipient. 
     
     
         47 . The method of  claim 1 , wherein said oligonucleotide or polypeptide is endogenous to said HUCPVC. 
     
     
         48 . The method of  claim 1 , wherein said oligonucleotide or polypeptide is not endogenous to said HUCPVC. 
     
     
         49 . The method of  claim 1  comprising administering at least two different HUCPVC populations, wherein each HUCPVC population has been genetically modified to increase the expression of an anti-cancer polypeptide in each HUCPVC population, wherein the anti-cancer polypeptide is different in each HUCPVC populations. 
     
     
         50 . The method of  claim 1 , wherein the HUCPVC is genetically modified to produce two different polypeptides that cooperate to provide an anti-cancer benefit to the subject. 
     
     
         51 . The method according to  claim 50 , wherein the two different polypeptides are an antibody light chain and an antibody heavy chain. 
     
     
         52 . The method of  claim 1 , wherein said HUCPVC is allogeneic to said subject. 
     
     
         53 . A kit, or an article of manufacture, comprising a human umbilical cord perivascular cell (HUCPVC) that has been genetically modified to increase the expression of an oligonucleotide or a polypeptide in said HUCPVC relative to a HUCPVC that has not been genetically modified, wherein said HUCPVC controls cancer in a recipient. 
     
     
         54 . A human umbilical cord perivascular cell that has been genetically modified for use in a method according to any one of  claims 1 - 52 . 
     
     
         55 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and genetically modified human umbilical cord perivascular cells according to  claim 54 , wherein said cells are present in a dose effective for use in accordance with a method according to any one of  claims 1 - 52 . 
     
     
         56 . An assemblage comprising individual and separate containers each comprising a HUCPVC population according to  claim 54 , and a catalog indexing the containers in the assemblage, wherein each HUCPVC is modified genetically to produce a different polypeptide useful in the treatment of cancer. 
     
     
         57 . The method according to any one of  claims 1 - 52 , wherein the cancer is selected from Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; Brain Tumors including Glioma; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma, Ependymoma, Medulloblastoma, and Supratentorial; Primitive Neuroectodermal Tumors; Brain Tumor, Visual Pathway and Hypothalamic Glioma; Breast Cancer; Bronchial Adenomas/Carcinoids; Carcinoid Tumor; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma; Cervical Cancer; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma; Epithelial Cancer, Ovarian Cancer; Esophageal Cancer; Ewing's Family of Tumors; Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Brain Stem Glioma; Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, (Primary); Hepatocellular (Liver) Cancer; Hodgkin's Lymphoma; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer; Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia; Lymphoblastic Leukemia; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's; Lymphoma, Non-Hodgkin's; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma; Malignant Thymoma; Medulloblastoma; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's Lymphoma; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma Sarcoma, Soft Tissue; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma; Thymoma, Malignant; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Liver and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. 
     
     
         58 . Use of a human umbilical cord perivascular cell according to  claim 54  for the treatment of cancer. 
     
     
         59 . In a frozen state, a human umbilical cord perivascular cell that has been genetically modified for use in a method according to any one of  claims 1 - 52 .